ICT-based adherence monitoring in kidney transplant recipients: a randomized controlled trial.

BACKGROUND: Prior studies have explored the use of regular reminders to improve adherence among kidney transplant recipients (KTRs), but none have included real-time alarms about drug dosage, frequency, and interval. In the present study, we aimed to evaluate the efficacy and stability of an information and communication technology (ICT)-based centralized monitoring system for increasing medication adherence among Korean KTRs. METHODS: In this prospective, multicenter, randomized controlled study, enrolled KTRs were randomized to either the ICT-based centralized monitoring group or control group. The ICT-based centralized monitoring system alerted both patients and medical staff with texts and pill box alarms if there was a missed dose or a dosage/time error. We compared the two groups in terms of medication adherence and transplant outcomes over 6 months, and evaluated patient satisfaction with the ICT-based monitoring system. RESULTS: Among 114 enrolled KTRs, 57 were assigned to the ICT-based centralized monitoring group and 57 to the control group. The two groups did not significantly differ in mean adherence at each follow-up visit. The intrapatient variability of tacrolimus and mycophenolic acid levels, renal function, and adverse transplant outcomes did not differ between the intervention and control groups, or between the intervention group with feedback generation and the intervention group without feedback generation. Patients showed high overall satisfaction with the ICT-based centralized monitoring system, which significantly improved across the study period (p = 0.012). CONCLUSIONS: Due to high baseline adherence, the ICT-based centralized monitoring system did not maximize medication adherence or enhance transplant outcomes among Korean KTRs. However, patients were highly satisfied with the system. Our results suggest that the ICT-based centralized monitoring system could be successfully applied in clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03136588. Registered 20 April 2017 - Retrospectively registered.

Estrogen-related receptor γ negatively regulates osteoclastogenesis and protects against inflammatory bone loss.

Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor that plays an important role in various metabolic processes under physiological and pathophysiological conditions. Here, we report that ERRγ functions as a negative regulator in receptor activator of nuclear factor κΒ ligand (RANKL)-induced osteoclast differentiation. We observed that ERRγ was strongly expressed in osteoclast precursors, bone marrow-derived macrophages (BMMs) while its expression was significantly reduced by RANKL during osteoclastogenesis. Overexpression of ERRγ in BMMs suppressed the formation of multinucleated osteoclasts and attenuated the induction of c-Fos and nuclear factor of activated T cells c1, which are critical modulators in osteoclastogenesis. Similarly, the treatment of ERRγ agonists, N-(4-(diethylaminobenzylidenyl)-N'-(4-hydroxybenzoyl)-hydrazine (DY131) or GSK4716, also inhibited osteoclast generation and the expression of these key modulators. On the other hand, shRNA-mediated knockdown of ERRγ accelerated the formation of bone-resorbing cells and the expression of osteoclastogenic markers. Forced expression of ERRγ blocked RANKL-stimulated phosphorylation of the nuclear factor κB (NF-κB) inhibitor IκBα and suppressed NF-κB transcriptional activity induced by RANKL or the NF-κB subunit p65. Furthermore, by employing a pharmacological approach, we showed that the ERRγ agonist DY131 protected against inflammatory bone loss induced by lipopolysaccharide in vivo. Together, our findings reveal that ERRγ is a pivotal regulator in RANKL-mediated osteoclastogenesis and suggest that ERRγ may have potential as a therapeutic target for pathological bone loss.

Detection of 13 Ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, Rg3, Rh2, F1, Compound K, 20(S)-Protopanaxadiol, and 20(S)-Protopanaxatriol) in Human Plasma and Application of the Analytical Method to Human Pharmacokinetic Studies Following Two Week-Repeated Administration of Red Ginseng Extract.

We aimed to develop a sensitive method for detecting 13 ginsenosides using liquid chromatography-tandem mass spectrometry and to apply this method to pharmacokinetic studies in human following repeated oral administration of red ginseng extract. The chromatograms of Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, Rg3, Rh2, F1, compound K (CK), protopanaxadiol (PPD), and protopanaxatriol (PPT) in human plasma were well separated. The calibration curve range for 13 ginsenosides was 0.5-200 ng/mL and the lower limit of quantitation was 0.5 ng/mL for all ginsenosides. The inter- and intra-day accuracy, precision, and stability were less than 15%. Among the 13 ginsenosides tested, nine ginsenosides (Rb1, Rb2, Rc, Rd, Rg3, CK, Rh2, PPD, and PPT) were detected in the human plasma samples. The plasma concentrations of Rb1, Rb2, Rc, Rd, and Rg3 were correlated with the content in red ginseng extract; however, CK, Rh2, PPD, and PPT were detected although they are not present in red ginseng extract, suggesting the formation of these ginsenosides through the human metabolism. In conclusion, our analytical method could be effectively used to evaluate pharmacokinetic properties of ginsenosides, which would be useful for establishing the pharmacokinetic-pharmacodymic relationship of ginsenosides as well as ginsenoside metabolism in humans.

G protein-coupled receptor 84 controls osteoclastogenesis through inhibition of NF-κB and MAPK signaling pathways.

GPR84, a member of the G protein-coupled receptor family, is found predominantly in immune cells, such as macrophages, and functions as a pivotal modulator of inflammatory responses. In this study, we investigated the role of GPR84 in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation. Our microarray data showed that GPR84 was significantly downregulated in osteoclasts compared to in their precursors, macrophages. The overexpression of GPR84 in bone marrow-derived macrophages suppressed the formation of multinucleated osteoclasts without affecting precursor proliferation. In addition, GPR84 overexpression attenuated the induction of c-Fos and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), which are transcription factors that are critical for osteoclastogenesis. Furthermore, knockdown of GPR84 using a small hairpin RNA promoted RANKL-mediated osteoclast differentiation and gene expression of osteoclastogenic markers. Mechanistically, GPR84 overexpression blocked RANKL-stimulated phosphorylation of IκBα and three MAPKs, JNK, ERK, and p38. GPR84 also suppressed NF-κB transcriptional activity mediated by RANKL. Conversely, GPR84 knockdown enhanced RANKL-induced activation of IκBα and the three MAPKs. Collectively, our results revealed that GPR84 functions as a negative regulator of osteoclastogenesis, suggesting that it may be a potential therapeutic target for osteoclast-mediated bone-destructive diseases.

Neuromedin B and its receptor silencing suppresses osteoclast generation by modulating precursor proliferation via M-CSF/c-Fms/D-type cyclins.

Neuromedin B (NMB), a mammalian bombesin-like peptide, regulates diverse physiological processes, such as energy metabolism, memory and fear behavior, and cellular growth, through its cognate receptor, NMBR. In this study, we report that NMB expression was upregulated during osteoclast development and that silencing NMB or NMBR attenuated osteoclast generation mediated by macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). We found that knockdown of NMB or NMBR using a small hairpin RNA suppressed M-CSF-induced proliferation of osteoclast precursor cells without altering osteoclast differentiation. Interestingly, NMB or NMBR knockdown reduced the expression of the M-CSF receptor, c-Fms, which is an important modulator of osteoclast development. Consequently, NMB or NMBR silencing inhibited M-CSF/c-Fms-mediated downstream signaling pathways like activation of ERK and Akt and induction of D-type cyclins, cyclin D1 and D2. Moreover, knockdown of NMB or NMBR accelerated apoptosis in osteoclast lineage cells by inducing caspase-3, caspase-9, and Bim expression. In summary, our study demonstrates that the NMB/NMBR axis plays a pivotal role in osteoclast generation by modulating the proliferation and survival of osteoclast lineage cells.

Pharmacokinetics and bioequivalence of a rosuvastatin/ezetimibe fixed-dose combination tablet versus single agents in healthy male subjects
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OBJECTIVE: The pharmacokinetic profiles and bioequivalence of a new rosuvastatin/ezetimibe fixed-dose combination (FDC; NVP-1205) vs. rosuvastatin and ezetimibe concomitantly administered as single agents were evaluated. MATERIALS AND METHODS: In this open-label, single-dose, crossover study (NCT02029625), eligible subjects were randomly assigned in a 1 : 1 ratio to receive a single dose of rosuvastatin (10 mg) with ezetimibe (10 mg) as either a FDC or as single agents concomitantly administered under fasted conditions, followed by a 2-week washout period and administration of the alternate formulation. Serial blood samples were collected predose and up to 96 hours postdose in each period for determination of plasma rosuvastatin and ezetimibe concentrations by liquid-chromatography tandem mass spectroscopy and calculation of pharmacokinetic parameters. RESULTS: The mean Cmax and AUC0-t values of rosuvastatin were 12.5 ng/mL and 115.6 ng×h/mL for the FDC, and 12.2 ng/mL and 115.1 ng×h/mL for the single agents concomitantly administered, respectively. The mean Cmax and AUC0-t values of ezetimibe were 4.7 ng/mL and 67.3 ng×h/mL for the FDC, and 4.5 ng/mL and 68.2 ng×h/mL for the single agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the rosuvastatin Cmax and AUC0-t were 106.20 (96.62 - 116.74) and 102.88 (96.32 - 109.90), respectively. The GMR and 90% CI for the ezetimibe Cmax and AUC0-t were 108.96 (98.56 - 120.51) and 98.13 (92.01 - 104.66), respectively. All treatments were well tolerated during this study, with no serious adverse events reported. CONCLUSION: The rosuvastatin/ezetimibe (10/10 mg) FDC was bioequivalent to single agents concomitantly administered. A single dose of rosuvastatin/ezetimibe as the FDC or as single agents was well tolerated.
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G Protein-Coupled Receptor 120 Signaling Negatively Regulates Osteoclast Differentiation, Survival, and Function.

G protein-coupled receptor 120 (GPR120) plays an important role in the regulation of inflammation and lipid metabolism. In this study, we investigated the role of GPR120 in osteoclast development and found that GPR120 regulates osteoclast differentiation, survival and function. We observed that GPR120 was highly expressed in osteoclasts compared to their precursors, bone marrow-derived macrophages (BMMs). Activation of GPR120 by its ligand GW9508 suppressed receptor activator of NF- κB ligand (RANKL)-induced osteoclast differentiation and the expression of nuclear factor of activated T cells c1 (NFATc1), a key modulator of osteoclastogenesis. GPR120 activation further inhibited the RANKL-stimulated phosphorylation of IκBα and JNK. In addition to osteoclast differentiation, GPR120 activation increased the apoptosis of mature osteoclasts by inducing caspase-3 and Bim expression. Activation of GPR120 also interfered with cell spreading and actin cytoskeletal organization mediated by M-CSF but not by RANKL. Coincident with the impaired cytoskeletal organization, GPR120 activation blocked osteoclast bone resorbing activity. Furthermore, knockdown of GPR120 using small hairpin RNA abrogated all these inhibitory effects on osteoclast differentiation, survival, and function. Together, our findings identify GPR120 as a negative modulator of osteoclast development that may be an attractive therapeutic target for bone-destructive diseases. J. Cell. Physiol. 231: 844-851, 2016. © 2015 Wiley Periodicals, Inc.

Pharmacokinetic drug interaction study using fimasartan and rosuvastatin in healthy volunteers.

OBJECTIVE: This study evaluated the possible pharmacokinetic interactions between rosuvastatin and fimasartan, an angiotensin II type 1 (AT1) receptor blocker (ARB), approved in Korea for the treatment of mild to moderate hypertension. METHODS: In this open-label, multiple-dose, two-period, single-sequence study, the enrolled subjects were randomized into two separate parts (A and B). In part A, subjects received 120 mg of fimasartan alone for 7 days during period I, and 120 mg fimasartan with 20 mg rosuvastatin for 7 days during period II. In Part B, subjects received rosuvastatin alone, followed by concomitant administration of fimasartan, with the same doses used as in Part A. There was a 7-day washout between periods I and II. Serial blood samples were collected for up to 48 hours for fimasartan and for up to 72 hours for rosuvastatin after the last dose of each period to determine the steady-state pharmacokinetics of both drugs. RESULTS: The mean Cmax,ss and AUCτ,ss values of fimasartan were 258.03 ± 176.75 ng/mL and 746.52 ± 273.49 ng×h/mL for fimasartan alone, and 289.40 ± 231.44 ng/mL and 848.43 ± 267.45 ng×h/mL for fimasartan and rosuvastatin coadministration, respectively (p-values for Cmax,ss and AUCτ,ss, 0. 513 and 0.006, respectively). The mean Cmax,ss and AUCτ,ss values of rosuvastatin were 9.94 ± 4.48 ng/mL and 85.29 ± 36.25 ng×h/mL for rosuvastatin alone and 11.94 ± 8.47 ng/mL and 77.33 ± 38.71 ng×h/mL for fimasartan and rosuvastatin coadministration, respectively (p-values for Cmax,ss and AUCτ,ss, 0.066 and 0.009, respectively). The geometric mean ratio (GMR) and 90% confidence intervals (CI) for the Cmax,ss and AUCτ,ss of fimasartan (with/without rosuvastatin) were 1.109 (0.813 - 1.511) and 1.159 (1.061 - 1.265), respectively. The GMR and 90% CI for the Cmax,ss and AUCτ,ss of rosuvastatin (with/without fimasartan) were 1.090 (0.979 - 1.213) and 0.870 (0.804 - 0.940), respectively. CONCLUSIONS: These results suggest that fimasartan and rosuvastatin have no relevant pharmacokinetic drug-drug interactions. All treatments were well tolerated during this study, with no serious adverse effects.
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Bioequivalence of a single 400-mg dose of imatinib 100-mg oral tablets and a 400-mg tablet in healthy adult Korean volunteers.

BACKGROUND: Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. A new once-daily 400-mg film-coated tablet of imatinib has been developed by a pharmaceutical company in Korea. OBJECTIVE: The present study was designed to assess and compare the PK parameters, bioavailability, and bioequivalence of the new imatinib 400-mg formulation (test) versus the conventional 100-mg formulation (reference) administered as a single 400-mg dose in healthy adult male volunteers. METHODS: This randomized, open-label, single-dose, two-way crossover study was conducted in healthy Korean male volunteers. Eligible subjects were randomly assigned in a 1 : 1 ratio to receive 400 mg of the test (one 400-mg tablet) or reference (four 100-mg tablets) formulation, followed by a 2-week washout period and administration of the alternate formulation. Serial blood samples were collected at 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours after administration. Plasma imatinib concentrations were determined using liquid chromatography coupled with tandem mass spectrometry. The formulations were to be considered bioequivalent if the 90% confidence intervals (CIs) of the adjusted geometric mean ratios for Cmax, AUC(0-t), and AUC(0-∞)ž were within the predetermined range of 0.80 - 1.25. RESULTS: In total, 35 subjects completed the study. No serious adverse event was reported during the study. The 90% CIs of the adjusted geometric mean ratios of the test formulation to the reference formulation for C(max), AUC(0-t) and AUC(0-∞)ž of imatinib were all within the bioequivalence criteria range of 0.8 - 1.25. CONCLUSIONS: The test formulation of imatinib met the Korean regulatory requirements for bioequivalence. Both imatinib formulations were well-tolerated in all subjects.

Alterations in Plasma Lipid Profile before and after Surgical Removal of Soft Tissue Sarcoma.

Soft tissue sarcoma (STS) is a relatively rare malignancy, accounting for about 1% of all adult cancers. It is known to have more than 70 subtypes. Its rarity, coupled with its various subtypes, makes early diagnosis challenging. The current standard treatment for STS is surgical removal. To identify the prognosis and pathophysiology of STS, we conducted untargeted metabolic profiling on pre-operative and post-operative plasma samples from 24 STS patients who underwent surgical tumor removal. Profiling was conducted using ultra-high-performance liquid chromatography-quadrupole time-of-flight/mass spectrometry. Thirty-nine putative metabolites, including phospholipids and acyl-carnitines were identified, indicating changes in lipid metabolism. Phospholipids exhibited an increase in the post-operative samples, while acyl-carnitines showed a decrease. Notably, the levels of pre-operative lysophosphatidylcholine (LPC) O-18:0 and LPC O-16:2 were significantly lower in patients who experienced recurrence after surgery compared to those who did not. Metabolic profiling may identify aggressive tumors that are susceptible to lipid synthase inhibitors. We believe that these findings could contribute to the elucidation of the pathophysiology of STS and the development of further metabolic studies in this rare malignancy.

Pattern recognition analysis for hepatotoxicity induced by acetaminophen using plasma and urinary 1H NMR-based metabolomics in humans.

Drug-induced liver injury (DILI) is currently an increasingly relevant health issue. However, available biomarkers do not reliably detect or quantify DILI risk. Therefore, the purpose of this study was to comparatively evaluate plasma and urinary biomarkers obtained from humans treated with acetaminophen (APAP) using a metabolomics approach and a proton nuclear magnetic resonance (NMR) platform. APAP (3 g/day, two 500 mg tablets every 8 h) was administered to 20 healthy Korean males (age, 20-29 years) for 7 days. Urine was collected daily before and during dosing and 6 days after the final dose. NMR spectra of these urine samples were analyzed using principal component analysis (PCA) and partial least-squares-discrimination analysis. Although the activities of aspartate aminotransferase and lactate dehydrogenase were significantly increased 7 days post-APAP treatment, serum biochemical parameters of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, γ-glutamyl transpeptidase, and lactate dehydrogenase were within normal range of hepatic function. However, urine and plasma (1)H NMR spectroscopy revealed different clustering between predosing and after APAP treatment for global metabolomic profiling through PCA. Urinary endogenous metabolites of trimethylamine-N-oxide, citrate, 3-chlorotyrosine, phenylalanine, glycine, hippurate, and glutarate as well as plasma endogenous metabolites such as lactate, glucose, 3-hydroxyisovalerate, isoleucine, acetylglycine, acetone, acetate, glutamine, ethanol, and isobutyrate responded significantly to APAP dosing in humans. Urinary and plasma endogenous metabolites were more sensitive than serum biochemical parameters. These results might be applied to predict or screen potential hepatotoxicity caused by other drugs using urinary and plasma (1)H NMR analyses.

Influence of hepatic dysfunction on the pharmacokinetics and safety of fimasartan.

This study was designed to assess the pharmacokinetics (PK) and safety of fimasartan, an angiotensin II type 1 receptor blocker, in hepatic impairment patients as compared with healthy subjects. An open-label, single-dose, parallel study was conducted in 6 healthy male volunteers and 12 subjects with hepatic impairment. Healthy subjects were matched with hepatic dysfunction patients on the basis of age, gender, and body weight. After a single 120-mg oral administration of fimasartan, PK parameters and safety were analyzed between the hepatic dysfunction groups and healthy group. Compared with the healthy subjects, the geometric mean ratio and 90% confidence intervals for the maximum plasma concentration and the mean area under the plasma concentration-time curve from 0 to infinity (AUC)inf were 0.77 (0.24-2.47) and 1.11 (0.50-2.46), respectively, for the mild hepatic impairment and 6.55 (3.56-12.03) and 5.17 (4.19-6.37), respectively, for moderate hepatic impairment. However, there was no significant difference in time to peak plasma concentration (t(max)) and elimination half-life, and there were no serious or severe adverse events in all subjects. Subjects with mild hepatic impairment exhibited similar bioavailability compared with healthy subjects, whereas subjects with moderate hepatic impairment seemed to exhibit a higher level of systemic exposure to fimasartan than healthy subjects. In addition, all subjects were tolerable with fimasartan.

Comparative Pharmacokinetic Profiles of a Novel Low-Dose Micronized Formulation of Raloxifene 45 mg (AD-101) and the Conventional Raloxifene 60 mg in Healthy Subjects.

Raloxifene hydrochloride shows poor bioavailability (only 2%) when orally administered because of its poor aqueous solubility and its extensive first-pass metabolism. A new micronized formulation of raloxifene was developed to improve bioavailability via enhanced gastrointestinal absorption. The primary objective of this study was to evaluate the pharmacokinetic characteristics of a new micronized raloxifene formulation (AD-101) in comparison with the conventional raloxifene formulation. This study was designed as an open-label, randomized, 2-treatment-period, crossover study with a 2-week washout period. Two treatments consisted of micronized raloxifene 45 mg daily; and conventional raloxifene 60 mg daily administered in fasting conditions. Plasma raloxifene concentrations were determined by a validated method using ultra-fast liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were calculated using a noncompartmental model. In total, 49 subjects completed the study. The geometric mean ratio (micronized/conventional) of the maximum concentration and the area under the plasma concentration-time curve from time zero to the last concentration values were 1.08 (90% CI, 0.95-1.24) and 0.97 (90% CI, 0.89-1.05), respectively. The adverse event profile did not differ between the 2 formulations. The results demonstrate that micronized formulation of raloxifene 45 mg is equivalent to conventional formulation of raloxifene 60 mg when administered at the single dose in the fasted state. After single oral dosing of AD-101, there were no serious or unexpected adverse events.

Metabolomic analysis of the inhibitory effect of phthalates and bisphenol A on the antioxidant activity of vitamin D in human samples using liquid chromatography-mass spectrometry.

Vitamin D is important because it has roles in maintaining musculoskeletal health, redox homeostasis, and the immune system; however, it is commonly dysregulated by endocrine disrupting chemicals, particularly phthalates and bisphenol A (BPA). Continuous exposure to phthalates and BPA may alter the endogenous metabolite profiles associated with vitamin D activity, although the specific metabolites are yet to be identified. In this study, we identified the endogenous metabolites altered by phthalates and BPA exposure through untargeted metabolic profiling and investigated the role of these metabolites in vitamin D activity. Plasma metabolic profiling using liquid chromatography-mass spectrometry was performed in two groups: severe 25-hydroxyvitamin D (25(OH)D) deficiency and high exposure to phthalates and BPA (Group A) and 25(OH)D deficiency and low exposure to phthalates and BPA (Group B). Multivariate analysis revealed a distinct separation between the two groups. A total of six metabolites were annotated, of which levels of two were significantly different between the two groups: platelet-activating factor (PAF) C16 or lysophosphatidylcholine (lysoPC) 18:0, and 11Z-eicosenamide. Plasma levels of PAF C16 or lysoPC 18:0 were increased in Group A and exhibited an area under the curve of 0.769 with an accuracy of 74.4% in a receiver operating characteristic curve analysis. These metabolites are generated as byproducts of lipid peroxidation, which supports the fact that phthalates and BPA induce oxidative stress in cells. Furthermore, PAF C16 and lysoPC 18:0 may be involved in the network that interferes with the antioxidant activity of vitamin D upon exposure to phthalates and BPA. This study results provide useful information on how the activity of vitamin D on the antioxidant system is inhibited when exposure to phthalates and BPA.

Fed and fasted bioequivalence assessment of two formulations of extended-release fixed-dose combination dapagliflozin/metformin (10/1,000 mg) tablets in healthy subjects.

Two open-label, randomized, two-period crossover studies were conducted to investigate the pharmacokinetic (PK) properties, safety, and bioequivalence of the test formulation (KD4004), a new fixed-dose combination (FDC) formulation of dapagliflozin and metformin extended release (XR) tablets, relative to the reference formulation (10 mg dapagliflozin/1,000 mg metformin XR FDC tablet) in healthy subjects under fasting (Part A) and fed (Part B) conditions. After giving the dose, serial blood samples were collected for a period of 48 hours. Primary PK parameters (AUC0-t and Cmax) were used to assess bioequivalence between two dapagliflozin/metformin XR (10/1,000 mg) FDC formulations under fed and fasting conditions. Safety and tolerability were also evaluated. Part A and Part B were completed by 32 and 37 subjects, respectively. Bioequivalence of the two FDC formulations of dapagliflozin and metformin XR tablets was established in both the fasted and the fed conditions as the 90% confidence interval of the ratios of adjusted geometric means for AUC0-t and Cmax were contained within the predefined range of 0.800-1.250 bioequivalence criteria. Single-dose administration of dapagliflozin and metformin XR was safe and well tolerated as the two FDC formulations. In conclusion, both FDC formulations of dapagliflozin and metformin XR tablets were bioequivalent in fed and fasted subjects. All treatments were well tolerated. Trial Registration: Clinical Research Information Service Identifier: KCT0004026.

Pharmacokinetics and Pharmacodynamics of YYD601, a Dual Delayed-Release Formulation of Esomeprazole, Following Single and Multiple Doses in Healthy Adult Volunteers Under Fasting and Fed Conditions.

Background: YYD601 was developed as a novel dual delayed release (DDR) formulation of esomeprazole to prolong the plasma esomeprazole concentration and extend the duration of acid suppression. Purpose: The pharmacokinetic (PK) and pharmacodynamics (PD) characteristics of YYD601 after single and multiple oral administrations were investigated in healthy Korean adults under fasting and fed conditions, and compared with the original esomeprazole capsule. Methods: In the single-center, randomized, open-label, parallel-design, two-period study, thirty two volunteers were enrolled into four dosing groups, including esomeprazole 40-mg (group A), YYD60130-mg (group B), YYD601 40-mg (group C), and YYD601 60-mg (group D) once daily for 5 days. Blood samples were collected for PK analysis, before and up to 24 h after dosing. For PD characteristics of YYD601, the percentages of time with intragastric pH > 4 over a 24-h period and during night-time following multiple oral administrations were evaluated. Results: A total of 27 subjects completed the study. YYD601 showed a dual-peak PK profile under fasting condition, with delayed Tmax, compared with conventional formulation. There were no significant differences in the AUC values adjusted for dose between the three YYD601 dosage groups and the conventional esomeprazole 40 mg. The esomeprazole AUC following single and multiple administration decreased with food intake by approximately 33%. YYD601 showed a linear pharmacokinetic profile in the dose range studied. There was no statistically significant difference in increase in mean percentage of time with intragastric pH > 4 for 24-hour and during night-time between the three different doses of YYD601 and the conventional formulation. The treatments were well-tolerated during the study and no serious adverse events were observed. Conclusion: YYD601 30 mg has a comparable effect on gastric acid inhibition as conventional esomeprazole 40 mg following once daily oral administration. Single and multiple oral dosing of YYD601 up to 60 mg were safe and well-tolerated throughout the study. Clinical Trial Registry: http://clinicaltrials.gov, NCT03558477 (date of registration: June 15, 2018; study period: between October 2017 and February 2018).

Pharmacokinetic Drug Interaction Between Raloxifene and Cholecalciferol in Healthy Volunteers.

Osteoporosis is a common skeletal disorder, often leading to fragility fracture. Combination therapy with raloxifene, a selective estrogen receptor modulator, and cholecalciferol (vitamin D3 ) has been proposed to improve the overall efficacy and increase compliance of raloxifene therapy for postmenopausal osteoporosis. To our knowledge, there has been no report of any study on the pharmacokinetic interaction between raloxifene and cholecalciferol. This study aimed to evaluate the possible pharmacokinetic interactions between raloxifene and cholecalciferol in healthy adult male Korean volunteers. Twenty subjects completed this open-label, randomized, single-dose, 3-period, 6-sequence, crossover phase 1 study with a 14-day washout period. Serial blood samples were collected from 20 hours before dosing to 96 hours after dosing. The plasma concentrations of raloxifene and cholecalciferol were determined using a validated method for high-performance liquid chromatography with tandem mass spectrometry. The geometric mean ratios (90%CIs) for area under the plasma concentration-time curve from time 0 to the last quantifiable time point and maximum plasma concentration of raloxifene with or without cholecalciferol were 1.02 (0.87-1.20) and 0.87 (0.70-1.08), respectively. For baseline-corrected cholecalciferol, geometric mean ratios (90%CIs) of area under the plasma concentration-time curve from time 0 to the last quantifiable time point and maximum plasma concentration with or without raloxifene were 1.01 (0.93-1.09) and 0.99 (0.92-1.06), respectively. Concurrent treatment with raloxifene and cholecalciferol was generally well tolerated. These results suggest that raloxifene and cholecalciferol have no clinically relevant pharmacokinetic drug-drug interactions when administered concurrently. All treatments were well tolerated, with no serious adverse events.

Lessons from a multicenter clinical trial with an approved wearable electrocardiogram: issues and practical considerations.

Although wearable electrocardiograms (ECGs) are being increasingly applied in clinical settings, validation methods have not been standardized. As an exploratory evaluation, we performed a multicenter clinical trial implementing an approved wearable patch ECG. Healthy male adults were enrolled in 2 study centers. The approved ECGs were deployed for 6 hours, and pulse rates were measured independently with conventional pulse oximetry at selected time points for correlation analyses. The transmission status of the data was evaluated by heart rates and classified into valid, invalid, and missing. A total of 55 subjects (40 in center 1 and 15 in center 2) completed the study. Overall, 77.40% of heart rates were within the valid range. Invalid and missing data accounted for 1.42% and 21.23%, respectively. There were significant differences in valid and missing data between centers. The proportion of missing data in center 1 (24.77%) was more than twice center 2 (11.77%). Heart rates measured by the wearable ECG and conventional pulse oximetry showed a poor correlation (intraclass correlation coefficient = 0.0454). In conclusion, we evaluated the multicenter feasibility of implementing wearable ECGs. The results suggest that systems to mitigate multicenter discrepancies and remove artifacts should be implemented prior to performing a clinical trial. Trial Registration: ClinicalTrials.gov Identifier: NCT05182684.

A randomized, open-label, single-dose, two-way crossover study to assess the pharmacokinetics between two tablets of fixed-dose combination formulation with raloxifene and cholecalciferol and concomitant administration of each agents in healthy male volunteers.

A new fixed-dose combination (FDC) formulation of raloxifene 60 mg and cholecalciferol 800 IU was developed to improve the medication compliance and overall efficacy of raloxifene treatment in postmenopausal osteoporosis patients. The aim of this study was to compare the pharmacokinetics between two tablets of FDC formulation of raloxifene/cholecalciferol and the two products administered concomitantly at respective doses. This randomized, open-label, single-dose, two-treatment, two-way crossover study included 46 volunteers. During each treatment period, subjects received the test formulation (FDC formulation containing raloxifene and cholecalciferol) or the reference formulation (co-administration of raloxifene and cholecalciferol), with a 14-d washout period. Serial blood samples were collected periodically over 96 hours after drug intake. In total, 46 subjects completed the study. The geometric mean ratios and its 90% confidence intervals of the FDC to the single agents for the area under the concentration-time curve from zero to the last quantifiable time point and the maximum plasma concentration met the regulatory criteria for bioequivalence: 1.1364 (1.0584-1.2201) and 1.1010 (0.9945-1.2188) for raloxifene and 1.0266 (0.9591-1.0989) and 1.0354 (0.9816-1.0921) for baseline-corrected cholecalciferol, respectively. Both formulations were well tolerated. No significant differences was observed in the incidence of adverse events between the two treatments. It was concluded that two tablets of the newly developed FDC formulation of raloxifene and cholecalciferol and the corresponding two agents administered concomitantly at respective doses were bioequivalent. Trial Registration: ClinicalTrials.gov Identifier: NCT03010267.

Clinical evaluation of efficacy and tolerability of HMC05 in healthy subjects with normal and high-normal blood pressure: a pilot study.

HMC05, a formulation containing eight different herbal extracts, has been used widely for several thousand years in China, Japan, and Korea as a remedy for hypertension and headache. Although its anti-inflammatory effects in mouse monocytic cell lines and anti-atherosclerotic effects in apoE-knockout mice have been reported, the pharmacodynamic effects of HMC05 in human subjects have not yet been investigated. We evaluated the efficacy and tolerability of this drug in 14 healthy male Korean subjects with normal or high-normal blood pressure (BP) in a randomized, single-blind, crossover study with a 2-week washout period. Four 500-mg tablets of HMC05 or placebo were orally administered three times daily to nine subjects with normal BP and five subjects with high-normal BP for 4 weeks. To assess the pharmacodynamic effects of HMC05, levels of high-sensitivity C-reactive protein and homocysteine, BP, and flow-mediated vasodilation were measured before and after the 4-week medication period with evaluation of tolerability. All 14 subjects completed the study, and HMC05 was well tolerated with no significant adverse events. HMC05 did not exhibit a significant BP-lowering effect in either BP group, and there were no significant differences in other pharmacodynamic values after HMC05 or placebo administration in the two groups. Further study is needed to evaluate the efficacy and tolerability of HMC05 in an adequate number of patients with hypertension.